Meta‐analysis argues for a female‐specific role of MAOA‐uVNTR in panic disorder in four European populations

Abstract

Panic disorder (PD) is a common mental disorder, ranking highest among the anxiety disorders in terms of disease burden. The pathogenesis of PD is multifactorial with significant heritability, however only a few convincing risk genes have been reported thus far. One of the most promising candidates is the gene encoding monoamine oxidase A (MAOA), due to its key role in monoaminergic neurotransmission, established validity of animal models, and the efficacy of MAO inhibitors in the treatment of PD. A promoter repeat polymorphism in MAOA (MAOA-uVNTR) impacts on gene expression; high-expression alleles have been reported to increase the risk for PD. To further scrutinize the role of this polymorphism, we performed a formal meta-analysis on MAOA-uVNTR and PD using original data from four published European (Estonian, German, Italian, and Polish) samples and genotypes from three hitherto unpublished German PD samples, resulting in the largest (n = 1,115 patients and n = 1,260 controls) genetic study on PD reported to date. In the unpublished samples, evidence for association of MAOA-uVNTR with PD was obtained in one of the three samples. Results of the meta-analysis revealed a significant and female-specific association when calculating an allelic model (OR = 1.23, P = 0.006). This sex-specific effect might be explained by a gene-dose effect causing higher MAOA expression in females. Taken together, our meta-analysis therefore argues that high-expression MAOA-uVNTR alleles significantly increase the risk towards PD in women. However, epigenetic mechanisms might obfuscate the genetic association, calling for ascertainment in larger samples as well as assessment of the MAOA promoter methylation status therein.

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

“…Genomic DNA of all individuals included in the case-control study was extracted from venous blood by a routine desalting method. The discovery sample was described previously 32 and consisted of 239 PD patients recruited in Germany (female=143, male=96; mean age 37.6+11.1). The diagnosis of PD and presence of comorbid agoraphobia (PD/AG; 68.6%; n=75) was ascertained by experienced psychiatrists on the basis of medical records and structured clinical interviews (Composite International Diagnostic Interview, CIDI) according to the criteria of DSM-III-R or DSM-IV, respectively [33][34][35] .…”

“…8) was obtained from the national research initive "Panic-Net" founded by the Federal Ministry of Education and Research 36 ; details on the sample as well as the study workflow were previously published 32,37 . The diagnosis of PD/AG (co-morbid AG was an inclusion criterion, so all patients suffered thereof) was established by a structured clinical interview (CIDI) according to DSM-IV criteria 35 .…”

Monoamine oxidase A (MAOA) gene polymorphism in offenders and psychiatric patients in an Egyptian Study

“…Also Lung et al [28] found that the 5-repeat allele had a low frequency (0.54% in males) with major depressive disorder. In addition, a low frequency of the 5-repeats allele was also observed in females with panic disorder [29].…”

Gender-Specific Association between the COMT Val158Met Polymorphism and Openness to Experience in Panic Disorder Patients

“…Gender-specific associations with depression have been shown in glutamate decarboxylase 1 gene single-nucleotide polymorphisms (SNPs) [1], α 2 -/β 2 -adrenoceptor gene polymorphisms [2], cAMP response element binding protein 1 [3] and monoamine oxidase A upstream variable number tandem repeat (MAOA-uVNTR) [4]. Associations between panic disorder and the glutamate decarboxylase 1 gene SNPs [5], MAOA-uVNTR [6] and neuropeptide S receptor gene [7] have also been detected.…”